In This Issue

OVERVIEW:
HOW IS ALCOHOL METABOLIZED BY THE BODY?

As alcohol
is broken down (or metabolized) by the body it generates a number of potentially
harmful byproducts. Those byproducts may lead to tissue damage, impairment of
other metabolic processes, even cancer and interaction with medications. In this
article, Dr. Samir Zakhari describes the various pathways of alcohol metabolism,
the enzymes involved and their genetic variations, as well as the effects of alcohol
metabolism and its byproducts on tissues and organs. Further research is needed
to clarify the mechanisms and effects of alcohol metabolism; this will lead to
intervention strategies that may help prevent its harmful effects.

ROLE
OF ACETALDEHYDE IN MEDIATING THE PHARMACOLOGICAL AND BEHAVIORAL EFFECTS OF ALCOHOL

Then
alcohol is metabolized in the body, it is first broken down to acetaldehyde. Acetaldehyde
accumulation outside the brain accounts for some of the adverse effects often
associated with drinking, including nausea and a “flushing response.”
In addition, acetaldehyde may mediate some of alcohol’s effects on the brain,
although the extent of this activity is controversial. Animal studies suggest
that low acetaldehyde levels in the brain may cause some of the same stimulating
and reinforcing effects as does alcohol consumption. Moreover, as with alcohol,
higher acetaldehyde levels have sedative effects. Some scientists therefore have
proposed that acetaldehyde, rather than ethanol itself, produces many of the effects
associated with drinking. Others, however, have argued that acetaldehyde levels
in the brain are negligible during normal alcohol consumption, even though the
alcohol-metabolizing enzyme catalase may produce acetaldehyde in parts of the
brain. Based on the available evidence, Dr. Etienne Quertemont and Mr. Vincent
Didone suggest that acetaldehyde likely has some direct effects on the brain and
mediates some of the effects observed after alcohol consumption; however, more
research is needed, especially to determine actual acetaldehyde concentrations
in the brain during normal drinking.

OXIDATION
OF ETHANOL IN THE BRAIN AND ITS CONSEQUENCES

Several
studies suggest that acetaldehyde, a toxic byproduct of alcohol metabolism, may
cause at least some of the behavioral effects of alcohol consumption. However,
it is unclear whether quantities of acetaldehyde in the brain are sufficient to
create these effects. Blood levels of acetaldehyde are very low during drinking,
and, even when they are significant, acetaldehyde has difficulty penetrating the
brain. This is because a unique barrier of cells protects the brain from harmful
substances in the blood stream. Additionally, subjects become intoxicated even
when acetaldehyde production is inhibited. However, these considerations become
irrelevant if it can be shown that acetaldehyde is produced within the brain.
Drs. Richard Deitrich, Sergey Zimatkin, and Sergey Pronko present evidence that
alcohol is in fact metabolized to acetaldehyde in the brain and that acetaldehyde
is responsible for at least some of alcohol’s behavioral effects.

ALCOHOL
METABOLISM’S DAMAGING EFFECTS ON THE CELL

The
enzyme cytochrome P450 2E1 (CYP2E1) is responsible for the metabolism of many
compounds into toxic byproducts. CYP2E1’s use of oxygen in alcohol metabolism
generates reactive oxygen species (ROS), which are highly reactive molecules that
can cause damage to cells and tissues. This article by Dr. Dennis R. Koop examines
the significant role CYP2E1 plays in generating ROS, leading to cell and tissue
damage. Understanding CYP2E1’s role in alcohol metabolism and the generation
of ROS is important to ultimately understanding alcohol-related tissue damage.

Acetaldehyde, a toxic byproduct
of alcohol metabolism, can cause a number of negative physical reactions—including
feelings of nausea and the flushing response. Acetaldehyde typically is converted
quickly to the nontoxic acetate in certain structures (i.e., the mitochondria)
of liver cells. This conversion is mediated by the enzyme aldehyde dehydrogenase
(ALDH). The faster and more efficiently ALDH reacts with acetaldehyde and other
molecules, the faster acetaldehyde is removed from the body. In this article,
Dr. Yedy Israel, Ms. María E. Quintanilla, Dr. Amalia Sapag, and Dr. Lutske
Tampier discuss two rat strains—the alcohol-abstaining UChA rats and the
alcohol-drinking UChB rats—that differ in the ALDH variants they carry as
well as in the activity of their mitochondria. These animals were used to study
the impact of ALDH and mitochondrial activity on alcohol metabolism and alcohol
consumption. The findings suggest that mitochondrial activity during alcohol metabolism
can regulate alcohol consumption not only in rats but in humans as well.

STUDYING
ALCOHOL ELIMINATION USING THE ALCOHOL CLAMP METHOD

Investigators
studying the effects of alcohol metabolism must contend with a number of potentially
confounding factors, such as the subject’s gender, ethnicity, genetic variations
in alcohol-metabolizing enzymes, and food consumption. One method that is helping
researchers gain a better understanding of how alcohol is metabolized is the alcohol
clamp method, in which alcohol is given intravenously. With this method, study
participants are able to achieve and maintain a target breath alcohol concentration
(BrAC) for an extended period of time. In this article, Drs.Vijay A. Ramchandani
and Sean O’Connor discuss the advantages of the alcohol clamp method, which
uses a computer model to estimate each individual’s specific alcohol elimination
rate based on each subject’s age, height, weight, and gender. The alcohol
clamp results in similar breath alcohol exposures in every subject and provides
a more direct assessment of alcohol metabolism in a steady state than can be achieved
by oral administration.

USE OF CULTURED CELLS
TO STUDY ALCOHOL METABOLISM

Cells that are grown
in a laboratory (i.e., cultured cells) are an important tool in studying how alcohol
damages the liver on a molecular level. Alcohol metabolism results in several
byproducts, and any of these byproducts, or an interaction between two or more
of these byproducts, might damage the liver. Cultured cells allow researchers
to investigate individual metabolic pathways, to control the cells’ exposure
to alcohol and its byproducts, to eliminate variables that might confound the
experiment, and to work with uniform (i.e., clonal) cells. Additionally, because
large quantities of cells can be cloned, researchers are able to repeat experiments
many times in order to confirm findings. Dr. Dahn L. Clemens describes important
findings that have been made possible by cultured cells and explores the strengths
and weaknesses of this research technique.

THE
ROLE OF NUTRITIONAL THERAPY IN ALCOHOLIC LIVER DISEASE

The
principal cause of alcoholic liver injury has been shown to be excessive alcohol
consumption; however, malnutrition is closely associated with the development
of alcoholic liver disease (ALD). Alcoholic patients may suffer from malnutrition
because they substitute calories from food with calories from alcoholic beverages,
because alcohol consumption interferes with the absorption of nutrients from the
gut, and because alcohol may alter the liver’s metabolism of sugar, fats,
and proteins. Drs. Christopher M. Griffith and Steven Schenker suggest that malnutrition
may contribute to some of the complications associated with ALD and that nutrition
repletion may improve some of these complications, particularly the increased
risk of infection associated with ALD. However, nutrition alone generally does
not improve survival rates; therefore, it is best administered in conjunction
with other treatments.